Schizophrenia risk conferred by rare protein-truncating variants is conserved across diverse human populations
Authors: Dongjing Liu, Dara Meyer, Brian Fennessy, Claudia Feng, Esther Cheng, Jessica S. Johnson, You Jeong Park, Marysia-Kolbe Rieder, Steven Ascolillo, Agathe de Pins, Amanda Dobbyn, Dannielle Lebovitch, Emily Moya, Tan-Hoang Nguyen, Lillian Wilkins, Arsalan Hassan, Henry S. Aghanwa, Moin Ansari, Aftab Asif, Rubina Aslam, Jose L. Ayuso, Tim Bigdeli, Stefano Bignotti, Julio Bobes, Bekh Bradley, Peter Buckley, Murray J. Cairns, Stanley V. Catts, Abdul Rashid Chaudhry, David Cohen, Brett L. Collins, Angèle Consoli, Javier Costas, Benedicto Crespo-Facorro, Nikolaos P. Daskalakis, Michael Davidson, Kenneth L. Davis, Faith Dickerson, Imtiaz A. Dogar, Elodie Drapeau, Lourdes Fañanás, Ayman Fanous, Warda Fatima, Mar Fatjo, Cheryl Filippich, Joseph Friedman, John F. Fullard, Penelope Georgakopoulos, Marianna Giannitelli, Ina Giegling, Melissa J. Green, Olivier Guillin, Blanca Gutierrez, Herlina Y. Handoko, Stella Kim Hansen, Maryam Haroon, Vahram Haroutunian, Frans A. Henskens, Fahad Hussain, Assen V. Jablensky, Jamil Junejo, Brian J. Kelly, Shams-ud-Din A. Khan, Muhammad N. S. Khan, Anisuzzaman Khan, Hamid R. Khawaja, Bakht Khizar, Steven P. Kleopoulos, James Knowles, Bettina Konte, Agung A. A. A. Kusumawardhani, Naeemullah Leghari, Xudong Liu, Adriana Lori, Carmel M. Loughland, Khalid Mahmood, Saqib Mahmood, Dolores Malaspina, Danish Malik, Amy McNaughton, Patricia T. Michie, Vasiliki Michopolous, Esther Molina, María D. Molto, Asim Munir, Gerard Muntané, Farooq Naeem, Derek J. Nancarrow, Amina Nasar, Tanvir Nasr, Jude U. Ohaeri, Jurg Ott, Christos Pantelis, Sathish Periyasamy, Ana G. Pinto, Abigail Powers, Belén Ramos, Nusrat H. Rana, Mark Rapaport, Abraham Reichenberg, Safaa Saker-Delye, Ulrich Schall, Peter R. Schofield, Rodney J. Scott, Megan Shanahan, Cynthia Shannon Weickert, Calvin Sjaarda, Heather J. Smith, Jose Javier Suárez-Rama, Muhammad Tariq, Florence Thibaut, Paul A. Tooney, Muhammad Umar, Elisabet Vilella, Mark Weiser, Jin Qin Wu, Robert Yolken, Katherine E. Burdick, Joseph D. Buxbaum, Enrico Domenici, Sophia Frangou, Annette M. Hartmann, Claudine Laurent-Levinson, Dheeraj Malhotra, Carlos N. Pato, Michele T. Pato, Kerry Ressler, Panos Roussos, Dan Rujescu, Celso Arango, Alessandro Bertolino, Giuseppe Blasi, Luisella Bocchio-Chiavetto, Dominique Campion, Vaughan Carr, Janice M. Fullerton, Massimo Gennarelli, Javier González-Peñas, Douglas F. Levinson, Bryan Mowry, Vishwajit L. Nimgaokar, Giulio Pergola, Antonio Rampino, Jorge A. Cervilla, Margarita Rivera, Sibylle G. Schwab, Dieter B. Wildenauer, Mark Daly, Benjamin Neale, Tarjinder Singh, Michael C. O’Donovan, Michael J. Owen, James T. Walters, Muhammad Ayub, Anil K. Malhotra, Todd Lencz, Patrick F. Sullivan, Pamela Sklar, Eli A. Stahl, Laura M. Huckins, Alexander W. Charney
Journal: Nature Genetics (2023)

Abstract Schizophrenia (SCZ) is a chronic mental illness and among the most debilitating conditions encountered in medical practice. A recent landmark SCZ study of the protein-coding regions of the genome identified a causal role for ten genes and a concentration of rare variant signals in evolutionarily constrained genes 1 . This recent study—and most other large-scale human genetics studies—was mainly composed of individuals of European (EUR) ancestry, and the generalizability of the findings in non-EUR populations remains unclear. To address this gap, we designed a custom sequencing panel of 161 genes selected based on the current knowledge of SCZ genetics and sequenced a new cohort of 11,580 SCZ cases and 10,555 controls of diverse ancestries. Replicating earlier work, we found that cases carried a significantly higher burden of rare protein-truncating variants (PTVs) among evolutionarily constrained genes (odds ratio = 1.48; P = 5.4 × 10 −6 ). In meta-analyses with existing datasets totaling up to 35,828 cases and 107,877 controls, this excess burden was largely consistent across five ancestral populations. Two genes ( SRRM2 and AKAP11 ) were newly implicated as SCZ risk genes, and one gene ( PCLO ) was identified as shared by individuals with SCZ and those with autism. Overall, our results lend robust support to the rare allelic spectrum of the genetic architecture of SCZ being conserved across diverse human populations.